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Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in  SCN1A , the gene encoding neuronal sodium channel Na v 1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Na v 1.1 in human inhibitory versus excitatory neurons. We studied a Na v 1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Na v 1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Na v 1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons.

A deleterious Na v 1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients